Jones M., Fleming S.A. Organic Chemistry

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16.13 Irreversible Addition Reactions: A General Synthesis of Alcohols 799

Like other Lewis bases, Grignard reagents, organolithium reagents, and metal

hydrides are also able to undergo addition to carbonyl-containing compounds.These

additions lead directly to the next subject.

16.13 Irreversible Addition Reactions: A General

Synthesis of Alcohols

Now that we know something of the structures of these organometallic reagents,

it is time to look at their reactivity with ketones and aldehydes. This subject is

important, because these reactions form carbon–carbon bonds, a central goal in

synthetic chemistry. Like oxygen- and nitrogen-centered nucleophiles, organometallic

reagents (and metal hydrides) add to carbonyl compounds. Although there is no free



(or H



) in these reactions, the organometallic reagents are reactive enough to

deliver an R



group, acting as a nucleophile, to the Lewis acidic carbon of the car-

bonyl group (Fig. 16.59). The initial product is a metal alkoxide, which is protonated

Addition

Protonation

MgX

Grignard

reagents

Organolithium

reagents

Metal alkoxides

Alcohols

Metal alkoxides

MgX

LiOH

HOMgX

Alcohols

–

Addition

Protonation

FIGURE 16.59 Organometallic reagents are strong enough nucleophiles to add to carbonyl

compounds. When water is added in a second step, alcohols are produced.

when the solution is neutralized by addition of aqueous acid in a second step.Water

cannot be present at the start of the reaction because it would destroy the

organometallic reagent (Fig. 16.60).

MgX

LiOH

HOMgX

FIGURE 16.60 If water is present at

the beginning of the reaction, the

organometallic reagent is destroyed

through hydrocarbon formation.

It is easy to make the mistake of writing this reaction sequence as shown in Figure

16.61a, which means, “Treat the ketone with a mixture of alkyllithium reagent and

water.”This procedure is impossible, because the water would destroy the alkyllithi-

um immediately (Fig. 16.60). The correct way to write the sequence is shown in

800 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

Figure 16.61b and means, “First allow the ketone to react with the alkyllithium

reagent and then, after some specified time, add water.”

RMgX

A primary

alcohol

MgX

1. RMgX

2. H

RCH

RMgX

MgX

RMgX

Secondary alcohols

MgBr

(60%)

RMgX

–

(69%)

GENERAL CASES

SPECIFIC EXAMPLES

MgCl

FIGURE 16.62 Reaction of

organometallic reagents with

formaldehyde, followed by hydrolysis,

leads to primary alcohols.The

reaction of other aldehydes with

organometallic reagents, followed by

hydrolysis, gives secondary alcohols.

LiOH+

RLi

(a)

(b)

FIGURE 16.61 Reaction (a) means,

Add a mixture of and water

to the carbonyl compound. Under

such conditions the organometallic

reagent will be destroyed. Reaction

(b) means, First add the

organometallic reagent to the

carbonyl compound and then, in a

second step, add water.

This addition of organometallic to carbonyl compounds gives us a new and most

versatile alcohol synthesis. Primary alcohols can be made through the reaction of an

organometallic reagent with formaldehyde (Fig. 16.62). Figure 16.62 also shows the

shorthand form of the reaction, which emphasizes the synthetic utility.

16.13 Irreversible Addition Reactions: A General Synthesis of Alcohols 801

Metal hydrides (LiAlH

, NaBH

, and many others) react in a similar fashion to

deliver hydride (H



) as the nucleophile (Fig. 16.64). Alcohols are formed when

water is added in a second, quenching step. Notice that this reaction is formally a

reduction. Aldehydes are reduced to primary alcohols and ketones are reduced to

secondary alcohols.There is no way to make a tertiary alcohol through this kind of

reduction (Fig. 16.64).

Similarly, reactions of organometallic reagents (RLi or RMgX) with alde-

hydes other than formaldehyde give secondary alcohols. The R of the organo-

metallic reagent can either be the same as that of the aldehyde or different

(Fig. 16.62).

Ketones react with Grignard reagents or organolithium reagents to give tertiary

alcohols. Three different substitution patterns are possible depending on the num-

ber of different R groups in the reaction (Fig. 16.63).

A SPECIFIC EXAMPLE

2. 0 ⬚C, H

1. CH

MgBr

ether

(95%)

MgX

RMgX

(or RLi)

RMgX

(or RLi)

RR R

MgX

RR R

MgX

RMgX

(or RLi)

RMgX

(or RLi)

RR R

MgX

RR R

–

THE GENERAL CASE

FIGURE 16.63 The reaction of ketones with organometallic reagents, followed

by hydrolysis, yields tertiary alcohols.

Grignard reaction

We have seen reduction of carbonyl compounds before. In Chapter 14 (p. 645),

we encountered the Clemmensen and Wolff–Kishner reductions in which a

carbon–oxygen double bond is reduced all the way to a methylene group.

802 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

OH, 20–30 ⬚C

–

LiAlH

(or NaBH

)

LiAlH

(or NaBH

)

LiAlH

(or NaBH

)

RRR

1. NaBH

(97%)

Methyl alcoholFormaldehyde

A primary

alcohol

A secondary

alcohol

2. H

THE GENERAL CASE

A SPECIFIC EXAMPLE

FIGURE 16.64 Metal hydride

addition, followed by hydrolysis, gives

primary alcohols from aldehydes and

secondary alcohols from ketones.

Carbonyl reduction

Summary

The irreversible addition of organometallic reagents and metal hydrides provides

a simple synthesis of primary, secondary, and tertiary alcohols. But you have to

be careful to choose your reagents properly, so that the desired substitution pat-

tern is achieved.

16.14 Oxidation of Alcohols to Carbonyl Compounds

16.14a Oxidation of Monoalcohols So far, we have generated two new and

very general alcohol syntheses, the reaction of aldehydes and ketones with

organometallic reagents, and the reduction of carbonyl compounds by metal

hydrides. A complement to the reduction reaction is the oxidation of alcohols to

aldehydes and ketones (Fig. 16.65). These oxidations extend the utility of the alco-

hol syntheses we have just learned, and complicate your life by increasing the

complexity of the molecules you are able to make.

16.14 Oxidation of Alcohols to Carbonyl Compounds 803

oxidation

reduction

oxidation

reduction

Reduction conditions: 1. LiAlH

(or NaBH

)

2. H

FIGURE 16.65 Alcohols can be

oxidized to carbonyl compounds.

This reaction is the reverse of what

you have just learned—the reduction

of carbonyl compounds to alcohols

through reactions with metal hydride

reagents.

No simple oxidation

products

OH O

3-Hexanone

(80%)

HOCH

CrO

pyridine

4-Isopropylbenzaldehyde

(83%)

CrO

Heptanoic acid

(70%)

FIGURE 16.66 Tertiary alcohols

cannot be easily oxidized, but

secondary and primary alcohols can

be. It is logical to infer that in order

for the oxidation reaction to succeed

there must be a carbon–hydrogen

bond available on the alcohol carbon.

Now your collection of syntheses can be extended by using the alcohols as starting

materials in making carbonyl compounds using the oxidation reaction. Tertiary alco-

hols cannot be easily oxidized, but primary and secondary ones can be. As shown in

Figure 16.66, secondary alcohols can only give ketones, but primary alcohols can give

either aldehydes or carboxylic acids (RCOOH) depending on the oxidizing agent used.

How do these oxidation reactions work? A typical oxidizing agent for primary alco-

hols is chromium trioxide (CrO

) in pyridine. As long as the reagent is kept dry, good

yields of aldehydes can often be obtained (Fig. 16.66). Although a metal–oxygen bond

is more complicated than a carbon–oxygen bond, the double bonds in CrO

and

804 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

react in similar ways. For example, an alcohol oxygen is a nucleophile and

can attack the chromium–oxygen bond to give, ultimately, a chromate ester inter-

mediate (Fig. 16.67). This reaction of a with an alcohol is analogous to the

formation of a hemiacetal from the reaction of a with an alcohol.C

proton

transfers

proton

transfers

RCH

Hemiacetal

RCH

A chromate ester

intermediate

–

FIGURE 16.67 Nucleophilic alcohols can add to bonds just as they do to bonds.

This reaction is the first step in the oxidation process, and in this case gives a chromate ester

intermediate.

OCr

Once the chromate intermediate is formed, pyridine (or any other base) initi-

ates an E2 reaction to give an aldehyde (an oxidized alcohol) and HOCrO



(a reduced chromium species) (Fig. 16.68).

Pyridine

HOCrO

–

FIGURE 16.68 The second step in the

oxidation reaction is a simple E2

reaction to generate the new

double bond.

No H available

for an E2 reaction!

CrO

FIGURE 16.69 A tertiary alcohol can

add to the double bond, but

there is no hydrogen in the chromate

intermediate available for an E2

reaction.

Chromium trioxide (CrO

) will also oxidize secondary alcohols to ketones. It

should now be clear why tertiary alcohols resist oxidation by this reagent. The ini-

tial addition reaction can proceed, but there is no hydrogen to be removed in the

elimination process (Fig. 16.69).

Alcohol oxidation

16.14 Oxidation of Alcohols to Carbonyl Compounds 805

100 ⬚C, 2 h

COOH

< 30 ⬚C

CrO

(94%)

(83%)

FIGURE 16.70 A typical reagent for

oxidation of secondary alcohols to

ketones is sodium dichromate in acid.

Other oxidizing agents also work.

Notice how this seemingly strange reaction, oxidation of alcohols with CrO

is really made up of two processes we have already encountered. The first step is

addition of an oxygen base to a chromium–oxygen double bond. The second step

is nothing more than a garden-variety elimination. The lesson here is that you

should not be bothered by the identity of the atoms involved.When you see a reac-

tion that looks strange, rely on what you already know. Make analogies, and more

often than not you will come out all right.That is exactly what all chemists do when

we see a new reaction. We think first about related reactions and try to find a way

to generalize.

Another useful oxidizing reagent is sodium chromate (Na

CrO

) or sodium

dichromate (Na

) in aqueous strong acid (Fig. 16.70). Under these aqueous

conditions, it is difficult to stop oxidation of primary alcohols at the aldehyde stage.

.. ..

....

RCH

Aldehyde

intermediate

CrO

Hydrated

aldehyde

A carboxylic

acid

.. ..

This hydrate

can be oxidized

FIGURE 16.71 Oxidation of a

primary alcohol leads to an aldehyde.

Aldehydes are hydrated in the

presence of water, and the hydrates

are alcohols. Further oxidation of the

hydrate leads to the carboxylic acid.

PROBLEM 16.23 Write a mechanism for the oxidation of a secondary alcohol to a

ketone by chromic oxide.

Overoxidation to the carboxylic acid almost always occurs. The difficulty is that

aldehydes are hydrated in water (p. 773). These hydrates are alcohols and can be

oxidized further (Fig. 16.71). If one wants to convert a primary alcohol into a car-

boxylic acid, Na

in H

and H

O is the reagent of choice.

806 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

MnO

pentane

(60%)

(79%)

(90%)

HNO

100 ⬚C

KMnO

COOH

25 ⬚C

(87%)

DMSO

(COCl)

CHO

FIGURE 16.72 Some oxidizing agents.

In addition to the chromium reagents, there are many other oxidizing agents of

varying strength and selectivity (Fig. 16.72). Manganese dioxide (MnO

) is effec-

tive at making aldehydes from allylic or benzylic alcohols, nitric acid (HNO

) oxi-

dizes primary alcohols to carboxylic acids, and potassium permanganate (KMnO

)

is an excellent oxidizer of secondary alcohols to ketones and of primary alcohols to

carboxylic acids, although it can be difficult to control. One of the mildest and most

useful oxidizing reagents is dimethyl sulfoxide (DMSO), which can be used in com-

bination with one of a variety of co-reactants to convert secondary alcohols into

ketones and primary alcohols into aldehydes.

Summary

Now we can reduce carbonyl compounds to the alcohol level with hydride reagents,

and oxidize them back again using the various reagents of this section. Although

one probably wouldn’t want to spend one’s life cycling a compound back and forth

between the alcohol and carbonyl stage, these reactions are enormously useful in

synthesis. Many alcohols are now the equivalent of aldehydes or ketones, because

they can be oxidized, and carbonyl compounds are the equivalent of alcohols because

they can be reduced with hydride or treated with an organometallic reagent.

PROBLEM 16.24 Starting from alcohols containing no more than three carbon atoms

and inorganic reagents of your choice, devise syntheses of the following molecules:

(a) (b) (c)

OH OH OH

(d) (e) (f)

16.15 Retrosynthetic Alcohol Syntesis 807

16.14b Oxidative Cleavage of Vicinal Diols There is an oxidation reaction

that works only for vicinal diols (1,2-diols). When a vicinal diol is oxidized by per-

iodic acid (HIO

) the diol is cleaved to a pair of carbonyl compounds (Fig. 16.73).

This reaction, which has long been used as a test for 1,2-diols, involves the forma-

tion of a cyclic periodate intermediate.

THE GENERAL CASE

A SPECIFIC EXAMPLE

HIO

R2R

HIO

(100%)

FIGURE 16.73 The cleavage of vicinal

diols by periodic acid.

HIO

O/H

Cyclic ester of periodic acid

O O

FIGURE 16.74 The vicinal diol

cleavage by periodic acid involves a

cyclic intermediate that breaks down

to give a pair of carbonyl compounds.

This reaction looks much like the formation of a cyclic acetal from a 1,2-diol

and a ketone.The intermediate breaks down to form the two carbonyl compounds.

As you can see from the mechanism (Fig. 16.74), only vicinal diols can undergo this

cleavage reaction.

PROBLEM 16.25 trans-1,2-Cyclohexanediol is much more reactive toward periodic

acid than the cis isomer. Explain why.

16.15 Retrosynthetic Alcohol Synthesis

It’s worth taking a moment to say a word again about strategy in doing synthe-

sis problems, and to reinforce an old idea. It is almost never a good idea to try to

see all the way back from the target molecule to the initial starting materials.

Chemists have learned to be much less ambitious and to work back one step at

a time. This process has been dignified with the title retrosynthetic analysis,

which makes the idea seem far more complicated than it is. Let’s assume you want

to make molecule A. The idea behind this retrosynthesis strategy is simply that

you can almost always see the synthetic step immediately leading to the product

A. That is, compound A could come from B. Sometimes the problem is one of

sorting among various possibilities of reactions that would lead to the product.

Each possibility might come from a different compound, so perhaps B, C, or D

are possible precursors to compound A. Now we just ask ourselves for a set of

Cleavage of vicinal diols

reactions leading to the new target B, or C, or D. The idea is that eventually this

technique will lead back to starting materials that are readily available. Don’t be

too proud to work back step by step, even in simple problems.

As an example of using retrosynthetic analysis, consider synthesizing a general

tertiary alcohol A (Fig. 16.75).It could be made in three ways.Your thoughts should

be led to each of the three ketones B, C, or D shown in the figure. You know the

retrosynthesis for the MgX. It comes from an X and Mg. To carry the analysis

further, you need to decide which ketone to use. Whichever one you choose, you

need to devise a synthesis for it. Fortunately, we have just covered this topic. You

know that a ketone can come from a secondary alcohol. So, B could be obtained

from the secondary alcohol E,which can come from an aldehyde F and MgX.The

beauty of it all is that aldehyde F comes from a primary alcohol G. So you will

inevitably find your way back to simple alcohols and alkyl halides in this analysis.

All that remains is to write out the forward reactions.

808 CHAPTER 16 Carbonyl Chemistry 1: Addition Reactions

MgX

FIGURE 16.75 A retrosynthetic

analysis of ways of making a tertiary

alcohol.

Note in Figure 16.75 that retrosynthetic analysis has appropriated a special arrow

for its own use. The double-lined arrow always points from the target molecule to

the immediate precursor. So a double-lined arrow pointing from A to B means that

A comes from B.

WORKED PROBLEM 16.26 Here is a specific example of using retrosynthetic analy-

sis. Provide a retrosynthetic synthesis of 2-phenyl-2-butanol.Assume that you have

benzene, ethanol, pyridine, and access to any inorganic reagents you might need.

ANSWER Here is the retrosynthetic analysis:

OHPh

O OOH OH

Li CH

Br CH

PhLi

PhBr

PhH

/FeBr

CrO

/pyridine

CONVENTION ALERT